Process for lowering high blood cholesterol levels



United Sta s Pa w 'o PROCESS FOR LOWERING HIGH BLOOD CHOLESTEROL LEVELS Jean Cottet and Joseph Redel,.Paris, France, assignors to Chimie et Atomistique, Paris, France, a French body corporate f v No Drawing. 7 Application June 15, 195

Serial No.436,973

7 Claims. Cl. 167- 65) The present invention relates to anew composition for lowering the cholesterol level in the bloodserum.

It is known that the normal cholesterol levelin the Claims priority, application Great Britain'June 19, 1953 Patented May 17, 1960 tional index such that the product of the latter and the .valence of M is equal to 1; the compound I is thus a neutral metallic salt generally readily tolerated by the organism. In certain cases, however, it is not advisable to use certain metallic salts when the cation such as sodium is prohibited in the'diet of the patient. .A --OB group, B being the cation of an organic base a such as piperazine; the compound I is then a readilyhuman blood serum as measured by the Grigaut and Liebermann method lies between 1.70 g. and 1.80 g. per a litre. Although a higher level than this is fairly common around the fiftieth year and does not seem to be always positively serious, in many cases an increase in the cholesterol level is a sign of pathological nutritive dis- Thus the cholesterol level may become abnormally high and attain 3 g. to'3.5 g, per litre and more. This might cause' if orders and of a disturbed metabolism.

not'remedied, grave vascular lesions. 1

Notwithstanding the many researches directed at 'dis covering an adequate remedy, present-day therapeutic: armament is very inadequate for counteracting this pathological increase in the cholesterol level..

we-have now discovered a really' efiicient compositio with which it is possible to lower the cholesterol level in- It has been found, somewhat surthe blood serum.

R represents an alkyl or aryl radical, R -represents hydrogen or an alkyl radical, R represents an alkyl or alkylene radical,

m is an integer equal to 0 or 1, and

X is a group satisfying the free valence of radical I very significantly lower the cholesterol level'in thehuman blood serum and render the compositions of Formula I readily tolerated by the human organism, when they are administered with an inert vehicle orally inthe form of tablets, through the rectum in the form ofsuppositories or parenterally in the form of solutions. K The invention has for objectt'o provide'anew composition for lowering the cholesterol level in'the' blood serum comprising 'a compound of Formula I mentioned above and an inert vehicle administrable in human medicine. v I

This inert vehicle in the case of'tablets comprises the tolerated aminated salt. v

A NH group, the compound I is then an amide., This form isparticularly advantageous since the amides are 7 not acidsand permit fairly often avoiding an intolerance from a digestive point of'view, are devoid'of metallic ions, which aresometimes contraindicated, and are but little hygroscopic.

The compounds of Formula I, in which R, R and R vary within the indicated limits, are all more or less active','

' "for the intended purpose depending on'the nature of the.

radicals R and R The preferred compounds are .those in which R is an alkylradical having 1 or 2 carbon atoms, :1 the radical phenyl or the radical naphthyl, R -is hydrogen,

. .or an alkyl radical having 1 to ,2 carbon atoms, R fis an In this way the second radical R is introduced.,

conventional mixture of starch, magnesium stearate and talc used in forming tablets. In the case of suppositories,

the vehicle is cocoa butter or any other conventional excipient. In the case of solutions the vehicle is wateror anappropriate solvent,

As has been mentioned above, the group X satisfying' nature of the. group X. The latter must merely be-such alkyl or alkylene radical having 1 to 7 carbon atoms.

The elements of Formula I" are generally"known, a certain number of them having been described in ,chern'i cal works. 7

The processes of preparing these compounds naturallyfi vary'with the nature of the- R, R or R2 substitu'entaj Owing to their great number it is not possible to'describe all of them in detail, which is inany case .un- .j..i. necessary since they are all based on conventional organic chemistrytprocesses. I

However, by way of example, we' shall 'give below details of a suitable process for certain. particular cases.

It comprise's,'m being equal to 0 andwhen R is a phenyl, R hydrogen, R an alkyl or an alkylene, preparing from phenylacetonitrile, C H CH CN, the... "sodium derivative C H 'CHNa-CN by the action of sodium amide and condensing this body with a halogenide which i s hydrolized so as-to replace the CN groupby a If R is also an alkyl radical it sufiices before effecting; thehydrolysis for replacing CN by COOH to subject the obtained compound to the same sequence of'operations,

The derivatives of Formula I have had heretofore very"- fewcommercial applications and in any case have never 1.: beenrecommended for therapeutical use in the form of a2 new'composition comprising the derivatives of Formula I- and the aforementioned inert vehicle in modifying the cholesterol level in the blood serum.

The new composition embodying the invention may be '3 to 6 of these tablets per day may be prescribed, according to the gravity of the case. The derivatives of Formula I are practically without toxicity and no contraindication opposes the administration thereof.

There will now be given some-clinical results obtained with the new composition in this particular tablet form, it being understood, as mentioned above, that other therapeutical forms may be used.

Phenylethylacetamide (compound of Formula I in which R e-phenyl, R =i-L R =ethyl, 171:0, X=NH has been tested on 102 patients in daily doses of 6 tablets of the aforementioned composition.

For the purpose of a better analysis of the effect of phenylethylacetarnide, the patientswere divided into five groups in accordance with the blood cholesterol level. For each group the mean blood cholesterol level was ascertained before treatment and then again in the course of the second, fourth, sixth and if desired the eighth week after the start of the treatment.

In the first group (6 patients having 'a cholesterol level exceeding 3.50 g'.), the mean cholesterol level dropped from 4.83 g. before treatment to 3.92 g. in the second week of the treatment, 2.93 g. in the fourth week and 2.87 g. in the sixth week; the drop in the cholesterol level was therefore 40% in 6 Weeks.

in the second group (18 patients having a cholesterol level between 3 g. and 3.49 g.), the mean cholesterol level dropped from 3.05 g. before treatment to 2.47 g. in the second week, 2.31 g. in the fourth week and 2.23 g. in the sixth week; the drop was therefore 26% in 6 weeks.

In the third group (34 patients having a cholesterol level between 2.50 g. and 2.99 g.), the mean cholesterol level dropped from 2.60 g. before treatment to 2.14 g. in the second week, 2.01 g. in the fourth week and 1.83 g. in'the sixth week; the drop was therefore 29% in 6 weeks. p p

In the fourth group (32 patients having a cholesterol level between 2 g. and 2.40 g.), the mean cholesterol level dropped from 2.17 g. before treatment to 1.90 g. in the second week, 1.93 g. in the fourth week and 1.82 g. in the sixth week; the drop was therefore 11% in six weeks.

In the fifth group (12 patients having a cholesterol levelbetween 1.50 g. and 1.99 g., i.e practically normal), the mean cholesterol-level dropped from 1.85 g. before treatment to 1.77 g. in the second week and 1.79 g. in the fourth week; the drop was therefore 3% in 4weeks.

As can be seen from the foregoing figures, the percentage drop is greater as the starting cholesterol level is higher. When the cholesterol level is normal, the composition has little effect.

The medicine was readily tolerated, the urinary functions always remained normal and there were no changes in the blood formula.

From the foregoing facts it is therefore possible to say that phenylethylacetamide normalizes the cholesterol level in the blood serum without seeming to lower it below the normal level.

Substantially similar results have been'obtained with sodium phenylethylacetate which differs from the foregoing composition only in the modification of the group X in ONa instead of NH;- as well as with other metallic salts or organic base salts of phenylethylacetic acid. From this it is clear that the active part of the composition is the radical of Formula II, the group X having no effect on the result except that the compounds of Formula I, being dependent on the nature of X, may be rendered more or less tolerated by the organism.

The. following Table I shows that in modifying the nature of the R, R, and R substituents and the value of the index m within the indicated limits, there are obtained products which also lower the cholesterol level in a noticeable manner. The lowering of the cholesterol level given in the last column of the table is a meanpercentage determined from a number of cases after treatment over a period of 6 weeks at the rate of 6 tablets per day of the aforementioned composition.

the ;;compositions 12, 13, 14, 15, and 16 respectively clearly shows that, if the radicals R, R and R and the index In remain-the same, the activity of the composition is practically independent of the nature of X.

Thisobservation is confirmed when X instead of being given the values ONa and NH is given the values OH, ()M,, and OB-previousl indicated, provided a neutralizing agent is added to the inert vehicle when X-OH.

Thus the invention provides an efficient composition for lowering the cholesterol level and thus contributes to therapeutic armament a new remedy. g This composition is indicated in all cases of high cholesterol level whatever the origin.

orders:

Arterial disorders -Atheromatosis and atherosclerosis Coronary artery disease (myocardial infarction) Angina pectoris Arteritis of the lower limbs Cerebral arteritis Aortitis Diabetes Familial xanthomatosis High blood pressure Lipoid nephrosis Chronic nephritis Hypothyroidism The invention is not limited to the described modes of carrying it into effect which have been given merely by way of example.

Having now described our invention what we claim as new and desire to secure by Letters Patent is:

composition comprising a pharmacologically-acceptable compound having the formula 15 wherein R is a member of the group consisting of the compositions 1, 2, 3, 4 and 11 with those obtained with It is particularly recommended in the following dis- 1. A process for lowering the cholesterol 'level in the allyl radical'and an alkyl radical having 1 to 7 carbon 1 atoms, m is an integer selected from the group consisting of and 1, and X is ananionic grouping selected from the group consisting of OH, OMe, OB, and

NH wherein Me is a pharmacologically acceptable alkali metal, and B is the cationof a pharmaeologicallyacceptable organic base, and an inert vehicle therefor.

2. A process for lowering the cholesterol level in the blood serum which comprises administering to a patient having an abnormally high blood cholesterol level, a

composition in dosage unit form comprising a solid phatmaceutical carrier and a significant amount of a pharmacologically-acceptable compound having the formula wherein R is a member of the group consisting of the allyl radical and an alkyl radical having lto 7 carbon atoms, In is an integer selected from the group consisting of 0 and 1, and X is an anionic grouping selectedfrom the group consisting of OH, OMe, OB, and .NH wherein Me is a pharmacologically acceptable alkali metal, and B is the cation of apharmacologically-acceptable organic base.

3. A process for lowering the cholesterol level in the blood serum which comprises administering to a patient having an abnormally high blood cholesterol level a composition comprising phenyl ethyl acetamide together with an inert vehicle therefor.

4. A process for lowering the cholesterol level in the blood serum which comprises administering to a patient having an abnormally high blood cholesterol level a composition comprising sodium phenyl ethyl acetate together with an inert vehicle therefor.

5. A process for lowering the cholesterol level in the blood serum which comprises administering to a patient having an abnormally high blood cholesterol level a composition comprising sodium phenyl allyl acetate together with an inert vehicle therefor.

6. A process for lowering the cholesterol level in the blood serum which comprisesv administering to a patient having an abnormally highblood cholesterol level a composition comprising sodium phenyl heptyl acetate'together with an inert vehicle therefor.

7. A process for lowering the cholesterol level in the Q Frankel: Die Arzneimittel-Synthese, 1927, Berlin, J.

Springer, 6th ed., pp. 522523.

Wakerlin: Annals Internal Med., August 1952, vol. 37,

No. 2, pp. 313-322.

Ludwig: Repertorium pharmazeutischer Spezial-Priiparate, Beobachter, Basel, 1948, 2nd ed., p. 464.

Houben: Fortschritte der Heilstofichemie, vol. II, Berlin, J. Springer, 1932, pp. 394-5.

La Presse Medicale, Nov. 14, 1953, vol. 61, No. 73, p. 1494.

Junkmann Jan. 16, 1940 L 

1. A PROCESS FOR LOWERING THE CHOLESTEROL LEVEL IN THE BLOOD SERUM WHICH COMPRISES ADMINISTERING TO A PATIENT HAVING AN ABNORMALLY HIGH BLOOD CHLOESTEROL LEVEL, A COMPOSITION COMPRISING A PHARMACOLOGICALLY-ACCEPTABLE COMPOUND HAVING THE FORMULA 